This invention relates to nitrate esters and use thereof in effecting neuroprotection, mitigating neurodegeneration and/or effecting cognition enhancement. More particularly, this invention relates to organic nitrates having therapeutic utility as neuroprotective agents and/or cognition enhancers. The invention still more particularly relates to nitrate esters bearing a sulfur or phosphorus atom xcex2 or xcex3 to a nitrate group and their congeners which have therapeutic utility as neuroprotective agents and/or cognition enhancers.
The nitrate ester glyceryl trinitrate (GTN) or nitroglycerin, has been used as a vasodilator in the treatment of angina pectoris for over a hundred years, and the dominant contemporary belief is that GTN exerts its therapeutic effect through in vivo release of nitric oxide (NO). Other organic nitrates, such as isosorbide dinitrate, have also been identified as effective and clinically important vasodilators. NO itself has been identified as Endothelium Derived Relaxing Factor (EDRF) and several classes of compounds, for example nitrosothiols, in addition to organic nitrates, have been proposed as NO donors or NO prodrugs. Well-known examples of these classes of compound and one nitrate, GTN itself, have been suggested to demonstrate neurotoxic or neuroprotective effects by dint of interactions with the redox modulatory site of the N-methyl-D-aspartate (NMDA) excitatory amino acid receptor. Thus GTN is firstly a potent vasodilator and secondly possesses potential neuroprotective properties. Several attempts have been made to increase the efficacy or potency of alternative organic nitrates as vasodilators relative to GTN, for example, by incorporation of propanolamine or cysteine functionalities. However, no attempt has been made to separately regulate the vasodilatory and neuroprotective effects of GTN. Indeed, postural hypotension, weakness and other signs of cerebral ischemia are adverse effects, associated with the vasodilatory effects of GTN and observed in treatment, which are highly contraindicative of GTN itself, and by extrapolation GTN derivatives (1,2,3-trinitratopropane derivatives), as clinically useful neuroprotective therapeutic agents.
In as much as the potent vasodilatory effects of organic nitrates may prove (a) deleterious to, or alternatively (b) synergistic with the neuroprotective effects of GTN, it is postulated herein that regulation of these two effects is required for development of new and useful neuroprotective therapeutic agents. Further, it is postulated that such regulation may be achieved through use of an appropriate organic nitrate, such as, for example, nitrate esters incorporating sulfur-containing or phosphorus-containing functionalities into the structure of the nitrate esters or through use of their congeners. Interaction of organic nitrates with amino acid neurotransmitter receptors, including the NMDA receptor, will provide examples of compounds with neuroprotective properties, but modulation of the xcex3-aminobutyric acid type A (GABAA) receptor response will provide examples of organic nitrates capable of cognition enhancement. Stimulation of cerebral soluble guanylyl cyclase (GCase) by organic nitrates, in particular selectively over arterial GCase, will provide examples of compounds with neuroprotective properties. Organic nitrates bearing antioxidant functionalities and those capable of inhibiting apoptosis will also provide examples of compounds with neuroprotective properties. These postulates are based, in part, on bioassay data on such compounds. Thus, there is a need for synthetic organic nitrates, such as, for example, nitrate esters containing sulfur or phosphorus functionalities or their congeners, as new and useful therapeutic agents for use in effecting neuroprotection, mitigating neurodegeneration and/or effecting cognition enhancement. It will be appreciated, therefore, that these compounds can be used for treatment conditions including but not limited to: stroke; Parkinson""s disease; Alzheimer""s disease; Huntington""s disease; multiple sclerosis; amylotrophic lateral sclerosis; AIDS-induced dementia; epilepsy; alcoholism; alcohol withdrawal; drug-induced seizures; viral/bacterial/fever-induced seizures; trauma to the head; hypoglycemia; hypoxia; myocardial infarction; cerebral vascular occlusion; cerebral vascular hemorrhage; hemorrhage; environmental excitotoxins of plant, animal and marine origin; dementias of all type, trauma, drug-induced brain damage, aging.
It is an object of the present invention to provide provide novel organic nitrates, including aliphatic nitrate esters bearing a sulfur or phosphorus moiety xcex2 or xcex3 to a nitrate group, or congeners thereof Another object of the present invention is to provide methods for making such novel organic nitrates. Another object of the invention is to provide methods for effecting neuroprotection, mitigating neurodegeneration and/or effecting cognition enhancement employing organic nitrates. Another object of the present invention is to provide novel drugs as neuroprotective agents. Yet another object of the present invention is to provide novel drugs for use in cognition enhancement.
This invention provides novel compounds, methods and pharmaceutical compositions which are useful in the treatment of neurological disorders requiring mitigation of neurodegeneration, neuroprotection and/or cognition enhancement. Methods of the invention involve administering to a subject in need thereof a therapeutic compound which provides neuroprotection or cognition enhancement. Accordingly, the compositions and methods of the invention are useful for effecting neuroprotection or cognition enhancement in disorders in which neurotoxic damage occurs. The methods of the invention can be used therapeutically to treat conditions including but not limited to: stroke; Parkinson""s disease; Alzheimer""s disease; Huntington""s disease; multiple sclerosis; amylotrophic lateral sclerosis; AIDS-induced dementia; epilepsy; alcoholism; alcohol withdrawal; drug-induced seizures; viral/bacterial/fever-induced seizures; trauma to the head; hypoglycemia; hypoxia; myocardial infarction; cerebral vascular occlusion; cerebral vascular hemorrhage; hemorrhage; environmental excitotoxins; dementias of all type, trauma, drug-induced brain damage, and aging or can be used prophylactically in a subject susceptible or predisposed to these conditions. In certain embodiments, a therapeutic compound used in the method of the invention preferably can interact with GCase effecting neuroprotection and/or cognition enhancement. In other embodiments, a therapeutic compound used in the method of the invention preferably can modulate glutamate and/or non-glutamate neuroreceptor interactions effecting neuroprotection and/or cognition enhancement.
The invention relates to organic nitrates, i.e., nitrate esters. In one aspect, the invention provides a method including the step of administering to a subject an effective amount of a therapeutic compound having the formula (Formula I): 
wherein E, F, G are organic radicals which may contain inorganic counterions, such that neurodegeneration is mitigated in the subject.
In another aspect, the invention provides a method including the step of administering To a subject an effective amount of a therapeutic compound having the formula (Formula I): 
wherein E, F, G are organic radicals which may contain inorganic counterions, such that cognition enhancement is effected.
In a further aspect, the invention provides use of therapeutic compounds that mitigate neurodegeneration, effect neuroprotection and/or effect cognition enhancement in a subject to which the therapeutic compound is administered, the compounds having the formula (Formula II): 
in which:
m and n and p are integers from 0 to 10;
R3,17 are each independently hydrogen, a nitrate group, or A;
R1,4 are each independently hydrogen or A;
where A is selected from: a substituted or unsubstituted aliphatic group (preferably a branched, or straight-chain aliphatic moiety having from 1 to 24 carbon atoms in the chain, which optionally contains O, S, NR6 and unsaturations in the chain, optionally bearing from 1 to 4 hydroxy, nitrate, amino or aryl, or heterocyclic groups; an unsubstituted or substituted cyclic aliphatic moiety having from 3 to 7 carbon atoms in the aliphatic ring, which optionally contains O, S, NR6 and unsaturations in the ring, optionally bearing from 1 to 4 hydroxy, nitrate, or amino or aryl, or heterocyclic groups; an unsubstituted or substituted aliphatic moiety constituting a linkage of from 0 to 5 carbons, between R1 and R3 and/or between R17 and R4, which optionally contains O, S, NR6and unsaturations in the linkage, and optionally bearing from 1 to 4 hydroxy, nitrate, amino or aryl, or heterocyclic groups); a substituted or unsubstituted aliphatic group (preferably a branched, cyclic or straight-chain aliphatic moiety having from 1 to 24 carbon atoms in the chain containing carbonyl linkages (e.g. Cxe2x95x90O, Cxe2x95x90S, Cxe2x95x90NOH), which optionally contains O, S, NR6 and unsaturations in the chain, optionally bearing from 1 to 4 hydroxy, nitrate, amino or aryl, or heterocyclic groups; a substituted or unsubstituted aryl group; a heterocyclic group; amino (including alkylamino, dialkylamino (including cyclic amino, diamino and triamino moieties), arylamino, diarylamino, and alkylarylamino); hydroxy; alkoxy; a substituted or unsubstituted aryloxy;
R2, R5, R18, R19 are optionally hydrogen, A, or Xxe2x80x94Y;
where X is F, Br, Cl, NO2, CH2, CF2, O, NH, NMe, CN, NHOH, N2H3, N2H2R13, N2HR13R14, N3, S, SCN, SCN2H2(R5)2, SCN2H3(R15), SC(O)N(R15)2, SC(O)NHR15, SO3M, SH, SR7, SO2M, S(O)R8, S(O)2R9, S(O)OR8, S(O)2OR9, PO2HM, PO3HM, PO3M2, P(O)(OR15)(OR16), P(O)(OR16)(OM), P(O)(R15)(OR8), P(O)(OM)R15, CO2M, CO2H, CO2R11, C(O), C(O)R12, C(O)(OR13), PO2H, PO2M, P(O)(OR14), P(O)(R13), SO, SO2, C(O)(SR13), SR5, SSR7 or SSR5;
Y is F, Br, Cl, CH3, CF2H, CF3, OH, NH2, NHR6, NR6R7, CN, NHOH, N2H3, N2H2R13, N2HR13R14, N3, S, SCN, SCN2H2(R15)2, SCN2H3(R15), SC(O)N(R15)2, SC(O)NHR15, SO3M, SH, SR7, SO2M, S(O)R8, S(O)2R9, S(O)OR8, S(O)2OR9, PO2HM, PO3M2, P(O)(OR15)(OR16), P(O)(OR16)(OM), P(O)(R15)(OR8), P(O)(OM)R15, CO2M, CO2H, CO2R11, C(O)R12, C(O)(OR13), C(O)(SR13), SR5, SSR7 or SSR5, or does not exist;
R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16 are the same or different alkyl or acyl groups containing 1-24 carbon atoms which may contain 1-4 ONO2 substituents; or C1-C6 connections to R1-R4 in cyclic derivatives, or are each independently hydrogen, a nitrate group, or W;
M is H, Na+, K+, NH4+, N+HkR11(4-k) where k is 0-3, or other pharmaceutically acceptable counterion;
and with the proviso that, when m=n=p=1; R19, R2, R18, R1=H; R17, R3 are nitrate groups; that R4 is not H or C1-C3 alkyl.
Preferred therapeutic compounds for use in the invention include compounds in which R19 is Xxe2x80x94Y. In some preferred embodiments: R19 is Xxe2x80x94Y and R5, R6, R8, R9, R10, R12, R13, R14, R15, R16 are the same or different alkyl groups containing 1-24 carbon atoms which may contain 1-4 ONO2 substituents, or C1 or C2 connections to R1-R3 in cyclic derivatives; R1 and R3 are the same or different and selected from H, C1-C4, alkyl chains, which may include one O, linking R1 and R3 to form pentosyl, hexosyl, cyclopentyl, or cycohexyl rings, which rings optionally bear hydroxyl substituents; R2 and R4 are the same or different and selected from H, a nitrate group, C1-C4 alkyl optionally bearing 1-3 nitrate group, and acyl groups (xe2x80x94C(O)R5); and R7, R11 are the same or different C1-C8, alkyl or acyl.
In certain embodiments in which R19 is Xxe2x80x94Y, m, p=1, and n=0.
In other embodiments in which R19 is Xxe2x80x94Y, X is selected from: CH2, O, NH, NMe, CN, NHOH, N2H3, N2H2R13, N2HR13R14, N3, S, SCN, SCN2H2(R15)2, SCN2H3(R15), SC(O)N(R15)2, SC(O)NHR15, SO3M, SH, SR7, SO2M, S(O)R8, S(O)2R9, S(O)OR8, S(O)2OR9, PO3HM, PO3M2, P(O)(OR15)(OR16), P(O)(OR16)(OM), P(O)(R15)(OR8), P(O)(OM)R15, CO2M, CO2H, CO2R11, C(O), C(O)R12, C(O)(OR13), PO2M, P(O)(OR14), P(O)(R13), SO, SO2, C(O)(SR13), and SSR4.
In other embodiments in which R19 is Xxe2x80x94Y, Y is selected from CN, N2H2R13, N2HR13R14, N3, SCN, SCN2H2 (R5)2, SC(O)N(R15)2, SC(O)NHR15, SO3M, SR4, SO2M, PO3HM, PO3M2, P(O)(OR15)(OR16), P(O)(OR16)(OM), P(O)(R15)(OR8), P(O)(OM)R15, CO2M, CO2H, CO2R11, C(O)R12, C(O)(SR13), SR5, SSR5, or does not exist.
In certain embodiments, X and/or Y contain a sulfur-containing functional group. In some embodiments, a compound of the invention according to Formula II comprises a heterocyclic functionality, more preferably, a nucleoside or nucleobase. In further embodiments, a compound of the invention comprises a carbocyclic functionality, more preferably, a steroidal or carbohydrate moiety.
In another aspect, a therapeutic compound which is employed in methods of the invention is represented by the formula (Formula III): 
in which: m is 1-10; R1-8, X, and Y have the meaning as defined above. In some embodiments, R6-R16 are the same or different alkyl or acyl groups containing 1-24 carbon atoms which may contain 1-4 ONO2 substituents, or C1-C6 connections to R1-R4 in cyclic derivatives. In certain preferred embodiments, R18 is A and n=1.
In another aspect, the invention provides novel compounds useful for mitigating neurodegeneration, effecting neuroprotection and/or effecting cognition enhancement which are represented by the structures of Formula 3.
In a further aspect, a therapeutic compound according to the invention is represented by the formula (Formula IV): 
in which: R3, R1=H; n, R2R4-18, X, and Y have the meaning as defined above. In certain preferred embodiments, X is CH2 or does not exist, and Y is selected from: F, Br, Cl, CH3, CF2H, CF3, OH, NH2, NHR6, NR6R7, CN, NHOH, N2H3, N2H2R13, N2HR13R14, N3, S, SCN, SCN2H2(R15)2, SCN2H3(R15), SC(O)N(R15)2, SC(O)NHR15, SO3M, SH, SR7, SO2M, S(O)R8, S(O)2R9, S(O)OR8, S(O)2OR9, PO2HM, PO3M2, P(O)(OR15)(OR16), P(O)(OR16)(OM), P(O)(R15)(OR8), P(O)(OM)R15, CO2M, CO2H, CO2R11, C(O)R12, C(O)(OR13), C(O)(SR13), SR5, SSR7 and SSR5. In certain embodiments, R2 and R4 are optionally H, a nitrate group or a connection to R5-R16 in cyclic derivatives.
By one particular aspect of this invention there is provided an aliphatic nitrate ester containing at least one nitrate group, in which a S or P atom is situated xcex2 or xcex3 to a nitrate group, or congeners thereof, having the general formula (Formula IV*): 
where X is CH2, O, NH, NMe, CN, NHOH, N2H3, N2H2R13, N2HR13R14, N3, S, SCN, SCN2H2(R5)2, SCN2H3(R5), SC(O)N(R5)2, SC(O)NHR5, SO3M, SH, SR7, SO2M, S(O)R8, S(O)2R9, S(O)OR8, S(O)2OR9, PO3M2, P(O)(OR,)(OR), P(O)(OR6)(OM), P(O)(R5)(OR8), P(O)(OM)R5, CO2M, CO2H, CO2R11, C(O), C(O)R12, C(O)(OR13), PO2M, P(O)(OR14), P(O)(R13), SO, SO2, C(O)(SR13), SR4, or SSR4;
Y is SCN, SCN2H2(R)2, SC(O)NHR5, SC(O)N(R5)2, SR4, SR10, SSR10, SO2M, SO3M, PO3HM, PO3M2, P(O)(OR5)(OR6), or P(O)(OR6)(OM), CN, N3, N2H2R13, N2HR13R14, CO2M, CO2H, CO2R11, C(O)R12, C(O)(SR13), or does not exist;
R5, R6, R8, R9, R10, R12, R13, R14, R15, R16, are the same or different alkyls containing 1-12 carbon atoms which may contain 1-4 ONO2 substituents or C1 or C2 connections to R1-R3 in cyclic derivatives;
R7, R11 are C1-C8, alkyl or acyl;
R2 and R4 are the same or different and selected from H, ONO2, C1-C4 alkyl optionally bearing 1-3 nitrate groups, and acyl groups (xe2x80x94C(O)R10);
R1 and R3 are the same or different and selected from H, C1-C4 alkyl and chains, which may rings optionally bear hydroxyl substituents; and
M is H, Na+, K include one O, linking R1 and R3 to form pentosyl, hexosyl, cyclopentyl or cycohexyl rings, which +, NH4+ or N+HnR11(4-n) where n is 0-3;
with the proviso that, when X is O, Y is not COR12; and
with the proviso that, when R3 is H, R6 is not ethyl or n-butyl;
and pharmaceutically acceptable salts thereof.
The invention further provides a pharmaceutical composition comprising an effective amount of nitrate ester of Formula IV*, in admixture with a physiologically acceptable carrier therefor. The invention still further provides a method for effecting neuroprotection in a subject in need thereof comprising administering to said subject an effective amount of a nitrate ester of Formula IV*.
In yet another aspect of the invention, compounds according to the invention are represented by the formula (Formula V): 
where m, n, R1-18, X, and Y have the meaning as defined above.
In another aspect, the invention provides methods for preparing organic nitrates represented by the structures of Formula V.
The therapeutic compounds of the invention are administered to a subject by a route which is effective for mitigating neurodegeneration, effecting neuroprotection and/or effecting cognition enhancement. Suitable routes of administration include sublingual, oral, buccal, transdermal, nasal, subcutaneous, intravenous, intramuscular and intraperitoneal injection. Preferred routes of administration are intravenous, subcutaneous and transdermal administration, particularly for effecting neuroprotection. In addition, for effecting cognition enhancement, oral administration may be preferred. The therapeutic compounds can be administered with a pharmaceutically acceptable vehicle.
The invention also provides methods for treating a disease state associated with neurodegeneration by administering to a subject an effective amount of a therapeutic compound having a formula as set forth above, such that a disease state associated with neurodegeneration is treated.
The invention provides methods for effecting neuroprotection and/or cognition enhancement by administering to a subject an effective amount of a therapeutic compound having a formula described above, such that neuroprotection and/or cognition enhancement is effected.
The invention further provides pharmaceutical compositions for treating neurodegeneration. The pharmaceutical compositions include a therapeutic compound of the invention in an amount effective to mitigate neurodegeneration in admixture with a pharmaceutically acceptable carrier therefor.
The invention also provides packaged pharmaceutical compositions for treating neurodegeneration. The packaged pharmaceutical compositions include a therapeutic compound of the invention and instructions for using the pharmaceutical composition for treatment of neurodegeneration.